The present invention relates to the production and recovery of taxane compounds. In particular, it relates to methods of identification and isolation of taxane-producing plant material.
Taxane compounds, in particular paclitaxel (Taxol.TM.), have significant antitumor activity and have been the focus of investigations to develop these compounds as drugs for the treatment of cancer. These compounds have also been shown to inhibit congenital polycystic kidney disease (Woo et al. Nature 368 759 (1994)). Paclitaxel, originally isolated from the bark of the Pacific yew, Taxus brevifolia, was recently approved by the Food and Drug Administration for use against ovarian cancer and has also shown activity against breast, lung and other cancers.
Continued testing of paclitaxel and other taxanes require quantities which cannot be obtained from the scarce natural source. T. brevifolia is a rare tree, grows slowly, and is not cultivated. In addition, thousands of pounds of bark are required to produce one pound of paclitaxel. Moreover, extraction of the bark is complicated, and product variability occurs.
Because of the scarcity of naturally occurring paclitaxel, numerous investigators have attempted to increase the supply of paclitaxel and other taxanes. For instance, cell suspension cultures of sporophytic tissues have been shown to produce paclitaxel (U.S. Pat. No. 5,019,504). In addition, recent reports describe the total synthesis of paclitaxel (see, Holton et al. JACS 116:1597 (1994) and Nicolaou et al. Nature 367:630 (1994). These syntheses, however, involve too many steps to be commercially feasible (Flann, Science 263:911 (1994)).
Increased availability of taxanes will facilitate investigations to synthesize analogs of paclitaxel or identify other taxanes with similar anti-tumor activity but having improved properties. For instance, paclitaxel is relatively insoluble in aqueous solutions. As a result, paclitaxel is usually dissolved in an oily base of castor oil and alcohol and administered in this form. The identification of related compounds with increased aqueous solubility could provide compounds with better cellular penetration and efficacy than is found with paclitaxel.
Despite advances in the art, availability of paclitaxel and other taxane compounds remains a critical limitation in further investigation and therapeutic use of these compounds. The present invention addresses these and other needs.